Christos Kiourtis, Maria Terradas-Terradas, Lucy M. Gee, Stephanie May, Anastasia Georgakopoulou, Amy L. Collins, Eoin D. O’Sullivan, David P. Baird, Mohsin Hassan, Robin Shaw, Ee Hong Tan, Miryam Müller, Cornelius Engelmann, Fausto Andreola, Ya-Ching Hsieh, Lee H. Reed, Lee A. Borthwick, Colin Nixon, William Clark, Peter S. Hanson, David Sumpton, Gillian Mackay, Toshiyasu Suzuki, Arafath K. Najumudeen, Gareth J. Inman, Andrew Campbell, Simon T. Barry, Alberto Quaglia, Christopher M. Morris, Fiona E. N. LeBeau, Owen J. Sansom, Kristina Kirschner, Rajiv Jalan, Fiona Oakley, Thomas G. Bird
{"title":"肝细胞衰老通过 TGFβ诱导多器官衰老和功能障碍","authors":"Christos Kiourtis, Maria Terradas-Terradas, Lucy M. Gee, Stephanie May, Anastasia Georgakopoulou, Amy L. Collins, Eoin D. O’Sullivan, David P. Baird, Mohsin Hassan, Robin Shaw, Ee Hong Tan, Miryam Müller, Cornelius Engelmann, Fausto Andreola, Ya-Ching Hsieh, Lee H. Reed, Lee A. Borthwick, Colin Nixon, William Clark, Peter S. Hanson, David Sumpton, Gillian Mackay, Toshiyasu Suzuki, Arafath K. Najumudeen, Gareth J. Inman, Andrew Campbell, Simon T. Barry, Alberto Quaglia, Christopher M. Morris, Fiona E. N. LeBeau, Owen J. Sansom, Kristina Kirschner, Rajiv Jalan, Fiona Oakley, Thomas G. Bird","doi":"10.1038/s41556-024-01543-3","DOIUrl":null,"url":null,"abstract":"Cellular senescence is not only associated with ageing but also impacts physiological and pathological processes, such as embryonic development and wound healing. Factors secreted by senescent cells affect their microenvironment and can induce spreading of senescence locally. Acute severe liver disease is associated with hepatocyte senescence and frequently progresses to multi-organ failure. Why the latter occurs is poorly understood. Here we demonstrate senescence development in extrahepatic organs and associated organ dysfunction in response to liver senescence using liver injury models and genetic models of hepatocyte-specific senescence. In patients with severe acute liver failure, we show that the extent of hepatocellular senescence predicts disease outcome, the need for liver transplantation and the occurrence of extrahepatic organ failure. We identify the TGFβ pathway as a critical mediator of systemic spread of senescence and demonstrate that TGFβ inhibition in vivo blocks senescence transmission to other organs, preventing liver senescence induced renal dysfunction. Our results highlight the systemic consequences of organ-specific senescence, which, independent of ageing, contributes to multi-organ dysfunction. Kiourtis et al. show that liver senescence triggers senescence and dysfunction in other organs through TGFβ secretion from the liver.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"26 12","pages":"2075-2083"},"PeriodicalIF":17.3000,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41556-024-01543-3.pdf","citationCount":"0","resultStr":"{\"title\":\"Hepatocellular senescence induces multi-organ senescence and dysfunction via TGFβ\",\"authors\":\"Christos Kiourtis, Maria Terradas-Terradas, Lucy M. Gee, Stephanie May, Anastasia Georgakopoulou, Amy L. Collins, Eoin D. O’Sullivan, David P. Baird, Mohsin Hassan, Robin Shaw, Ee Hong Tan, Miryam Müller, Cornelius Engelmann, Fausto Andreola, Ya-Ching Hsieh, Lee H. Reed, Lee A. Borthwick, Colin Nixon, William Clark, Peter S. Hanson, David Sumpton, Gillian Mackay, Toshiyasu Suzuki, Arafath K. Najumudeen, Gareth J. Inman, Andrew Campbell, Simon T. Barry, Alberto Quaglia, Christopher M. Morris, Fiona E. N. LeBeau, Owen J. Sansom, Kristina Kirschner, Rajiv Jalan, Fiona Oakley, Thomas G. Bird\",\"doi\":\"10.1038/s41556-024-01543-3\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"Cellular senescence is not only associated with ageing but also impacts physiological and pathological processes, such as embryonic development and wound healing. Factors secreted by senescent cells affect their microenvironment and can induce spreading of senescence locally. Acute severe liver disease is associated with hepatocyte senescence and frequently progresses to multi-organ failure. Why the latter occurs is poorly understood. Here we demonstrate senescence development in extrahepatic organs and associated organ dysfunction in response to liver senescence using liver injury models and genetic models of hepatocyte-specific senescence. In patients with severe acute liver failure, we show that the extent of hepatocellular senescence predicts disease outcome, the need for liver transplantation and the occurrence of extrahepatic organ failure. We identify the TGFβ pathway as a critical mediator of systemic spread of senescence and demonstrate that TGFβ inhibition in vivo blocks senescence transmission to other organs, preventing liver senescence induced renal dysfunction. Our results highlight the systemic consequences of organ-specific senescence, which, independent of ageing, contributes to multi-organ dysfunction. Kiourtis et al. show that liver senescence triggers senescence and dysfunction in other organs through TGFβ secretion from the liver.\",\"PeriodicalId\":18977,\"journal\":{\"name\":\"Nature Cell Biology\",\"volume\":\"26 12\",\"pages\":\"2075-2083\"},\"PeriodicalIF\":17.3000,\"publicationDate\":\"2024-11-13\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.nature.com/articles/s41556-024-01543-3.pdf\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Nature Cell Biology\",\"FirstCategoryId\":\"99\",\"ListUrlMain\":\"https://www.nature.com/articles/s41556-024-01543-3\",\"RegionNum\":1,\"RegionCategory\":\"生物学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CELL BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Nature Cell Biology","FirstCategoryId":"99","ListUrlMain":"https://www.nature.com/articles/s41556-024-01543-3","RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
Hepatocellular senescence induces multi-organ senescence and dysfunction via TGFβ
Cellular senescence is not only associated with ageing but also impacts physiological and pathological processes, such as embryonic development and wound healing. Factors secreted by senescent cells affect their microenvironment and can induce spreading of senescence locally. Acute severe liver disease is associated with hepatocyte senescence and frequently progresses to multi-organ failure. Why the latter occurs is poorly understood. Here we demonstrate senescence development in extrahepatic organs and associated organ dysfunction in response to liver senescence using liver injury models and genetic models of hepatocyte-specific senescence. In patients with severe acute liver failure, we show that the extent of hepatocellular senescence predicts disease outcome, the need for liver transplantation and the occurrence of extrahepatic organ failure. We identify the TGFβ pathway as a critical mediator of systemic spread of senescence and demonstrate that TGFβ inhibition in vivo blocks senescence transmission to other organs, preventing liver senescence induced renal dysfunction. Our results highlight the systemic consequences of organ-specific senescence, which, independent of ageing, contributes to multi-organ dysfunction. Kiourtis et al. show that liver senescence triggers senescence and dysfunction in other organs through TGFβ secretion from the liver.
期刊介绍:
Nature Cell Biology, a prestigious journal, upholds a commitment to publishing papers of the highest quality across all areas of cell biology, with a particular focus on elucidating mechanisms underlying fundamental cell biological processes. The journal's broad scope encompasses various areas of interest, including but not limited to:
-Autophagy
-Cancer biology
-Cell adhesion and migration
-Cell cycle and growth
-Cell death
-Chromatin and epigenetics
-Cytoskeletal dynamics
-Developmental biology
-DNA replication and repair
-Mechanisms of human disease
-Mechanobiology
-Membrane traffic and dynamics
-Metabolism
-Nuclear organization and dynamics
-Organelle biology
-Proteolysis and quality control
-RNA biology
-Signal transduction
-Stem cell biology